1. Field of the Invention
The present invention is substituted 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (X) which are useful for treating anxiety, depression and other CNS disorders in humans and animals.
2. Description of the Related Art
U.S. Pat. No. 3,652,588 discloses 6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were useful for tranquilizing and sedating mammals to suppress hunger in mammals. This document discloses that there can be substitution at the 9-position. However, those substituents are limited to hydrogen, alkyl, alkoxy and halogen.
U.S. Pat. No. 3,839,357 discloses 6-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were useful for tranquilizing mammals. This document discloses that there can be substitution at the 9-position. However, those substituents are limited to hydrogen, alkyl, alkoxy and halogen.
U.S. Pat. No. 3,676,558 discloses 6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were useful to suppress hunger in mammals. This document discloses that there can be substitution at the 9-position. However, it is limited to hydrogen, alkyl, alkoxy and halogen.
Disclosed is a 9-arylsulfone of the formula (XII) 
where R3 is:
(1) xe2x80x94H,
(2) C1-C4 alkyl,
(3) C0-C4-xcfx86 where the xe2x88x92xcfx86 substituent is optionally substituted with 1 or 2
(a) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I,
(b) xe2x80x94Oxe2x80x94R3-1 where R3-1 is:
xe2x80x94H,
C1-C4 alkyl,
xe2x80x94xcfx86,
(c) xe2x80x94CF3,
(d) xe2x80x94COxe2x80x94NR3-2R3-3 where R3-2 and R3-3 are xe2x80x94H and C1-C4 alkyl, and where R3-2 and R3-3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl,
(e) xe2x80x94NHxe2x80x94SO2xe2x80x94R3-4 where R3-4 is xe2x80x94H and C1-C4 alkyl,
(f) xe2x80x94NR3-2R3-3 where R3-2 and R3-3 are as defined above,
(g) xe2x80x94NR3-4xe2x80x94COxe2x80x94R3-4 where R3-4 is as defined above,
(h) xe2x80x94SO2xe2x80x94NR3-2R3-3 where R3-2 and R3-3 are as defined above,
(I) xe2x80x94Cxe2x89xa1N,
(j) xe2x80x94NO2,
where RN is:
(1) xe2x80x94H,
(2) C1-C4 alkyl,
(3) C0-C4-xcfx86 where the xe2x80x94xcfx86 substituent is optionally substituted with 1 or 2
(a) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I,
(b) xe2x80x94Oxe2x80x94RN-1 where RN-1 is
xe2x80x94H,
C1-C4 alkyl,
xe2x80x94xcfx86,
(c) xe2x80x94CF3,
(d) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are xe2x80x94H and C1-C4 alkyl, and where R3-2 and R3-3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl,
(e) xe2x80x94NHxe2x80x94SO2xe2x80x94RN-4 where RN-4 is xe2x80x94H and C1-C4 alkyl,
(f) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(g) xe2x80x94NRN-4xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(h) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(I) xe2x80x94Cxe2x89xa1N,
(j) xe2x80x94NO2,
where Rx is:
(1) xe2x80x94H
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I,
(3) xe2x80x94Oxe2x80x94Rxxe2x88x921 where Rxxe2x88x921 is:
xe2x80x94H,
C1-C4 alkyl,
xe2x80x94xcfx86,
(4) xe2x80x94CF3,
(5) xe2x80x94COxe2x80x94NRxxe2x88x922Rxxe2x88x923 where Rxxe2x88x922 and Rxxe2x88x923 are as defined above,
(6) xe2x80x94NHxe2x80x94SO2xe2x80x94Rxxe2x88x924 where Rxxe2x88x924 is as defined above,
(7) xe2x80x94NRxxe2x88x922Rxxe2x88x923 where Rxxe2x88x922 and Rxxe2x88x923 are as defined above,
(8) xe2x80x94NRxxe2x88x924xe2x80x94COxe2x80x94Rxxe2x88x924 where Rxxe2x88x924 is as defined above,
(9) xe2x80x94SO2xe2x80x94NRxxe2x88x922Rxxe2x88x922 where Rxxe2x88x922 and Rxxe2x88x923 are as defined above,
(10) xe2x80x94Cxe2x89xa1N,
(11) xe2x80x94NO2;
where R9 is:
(1) xe2x80x94H,
(2) xe2x80x94F, xe2x80x94Cl,
(3) C1-C4 alkyl,
(4) C1-C3 alkoxy,
(5) xe2x80x94CF3,
(6) C0-C4-xcfx86 where the xe2x80x94xcfx86 substituent is optionally substituted with 1 or 2
(a) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I,
(b) xe2x80x94Oxe2x80x94R9-1 where R9-1 is:
xe2x80x94H,
C1-C4 alkyl,
xe2x80x94xcfx86,
(c) xe2x80x94CF3,
(d) xe2x80x94COxe2x80x94NR9-2R9-3 where R9-2 and R9-3 are xe2x80x94H and C1-C4 alkyl, and where R9-2 and R9-3 are taken with the attached nitrogen atom to form a ring selected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl,
(e) xe2x80x94NHxe2x80x94SO2xe2x80x94R9-4 where R9-4 is xe2x80x94H and C1-C4 alkyl,
(f) xe2x80x94NR9-2R9-3 where R9-2 and R9-3 are as defined above,
(g) xe2x80x94NR9-4xe2x80x94COxe2x80x94NR9-4 where R9-4 is as defined above,
(h) xe2x80x94SO2xe2x80x94NR9-2R9-3 where R9-2 and R9-3 are as defined above,
(I) xe2x80x94Cxe2x89xa1N,
(j) xe2x80x94NO2 
(7) xe2x80x94OR9-1 where R9-1 is as defined above,
(8) xe2x80x94COxe2x80x94NR9-2R9-3 where R9-2 and R9-3 are as defined above,
(9) xe2x80x94NR9-2R9-3 where R9-2 and R9-3 are as defined above,
(10) xe2x80x94NHxe2x80x94SO2xe2x80x94NR9-4 where R9-4 is as defined above,
(11) xe2x80x94NHxe2x80x94CO2xe2x80x94R9-2 where R9-2 is as defined above,
and pharmaceutically acceptable salts thereof.
Also disclosed are compounds which are intermediates in the production of the 9-arylsulfones (XII), the thio ethers of formula (III), the amines of formula (IV), the hydrazines of formula (V), the compounds of formula (VII) and the protected 9-arylsulfones of formula (VIII) where PG is selected from the group consisting of xcfx86xe2x80x94CH2xe2x80x94, xcfx86xe2x80x94COxe2x80x94, xcfx86xe2x80x94CH2xe2x80x94CO2xe2x80x94 and xe2x80x94COxe2x80x94Oxe2x80x94C(CH3)3 and where R9 and Rx are as defined above.
Further disclosed is a method of treating a human who has a condition selected from the group consisting of anxiety, depression, schizophrenia, stress related disease, panic, a phobia, obsessive compulsive disorder, obeisity, post-traumatic stress syndrome who is in need of such treatment which comprises administering an effective amount of a 9-arylsulfone of the formula (XII).
The unsubstituted 9-arylsulfones (IX) and substituted 9-arylsulfones (X) are both prepared by means known to those skilled in the art. The term 9-arylsulfones (XII) includes both the unsubstituted 9-arylsulfones (IX), where R3 is xe2x80x94H and substituted 9-arylsulfones (X) where R3 is xe2x89xa0 to xe2x80x94H. The process of preparation can be viewed as being in two parts. The first part is the production of the appropriately substituted hydrazone (V), see CHART A. The second part is the coupling and reaction of the appropriately substituted hydrazone (V) with the 1-protected hexahydro-4H-azepine-4-one (VI) to give the intermediate (VII) and its transformation to the unsubstituted 9-arylsulfone (IX), see CHART B.
The appropriately substituted thiols (I) are either known to those skilled in the art or can be readily prepared from known starting materials by means well known to those skilled in the art. There can be either one or two R9 substituents and R9 includes xe2x80x94H, xe2x80x94F, xe2x80x94Cl, C1-C3 alkyl, C1-C3 alkoxy and xe2x80x94CF3; it is preferred that R9 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, C1 alkyl, C1 alkoxy, and xe2x80x94CF3 and when F- it is preferred that it be in the 4- or p-position. It is preferred that the R9 substituent be in either the 3- or 4-position.
The appropriately substituted thiol (I) is coupled with the appropriately substituted 4-chloro-1-nitrobenzene (II) by known means to produce the thioether (III). There can be either one or two Rx groups. If Rx is other than xe2x80x94H, it should be part of the 4-chloro-1-nitrobenzene (II) so that it will become part of the final unsubstituted 9-arylsulfone (IX) when it is formed. It is most difficult to add the Rx substitutent (other than xe2x80x94H) to the unsubstituted 9-arylsulfone (IX) once it is formed. Therefore, the Rx group should be part of the appropriately substituted 4-chloro-1-nitrobenzene (II) when it is reacted with the thiol (I). Rx includes of xe2x80x94H, xe2x80x94F and xe2x80x94Cl; it is preferred that Rx is xe2x80x94H. The thioether (III) is then oxidized with hydrogen peroxide (30%) followed by reduction with rhodium on carbon (5%), all of which is known to those skilled in the art, to produce the amine (IV). The amine (IV) is then diazotized by (sodium) nitrite and (hydrochloric) acid followed by reduction with tin chloride/water to give the corresponding hydrazine (V).
The second part of the reaction, is well known to those skilled in the art, see U.S. Pat. Nos. 3,652,588, 3,676,558 and 3,839,357. The only difference between the process in those patents and that here is the arylsulfone substituent at the 9-position. That substituent is already in place in the hydrazine (V) prior to the reaction of the 9-arylsulfone hydrazine (V) with the 1-protected hexahydro-4H-azepine-4-one (VI) to produce the correspondingly substituted intermediate (VII). Suitable protecting groups (PG) include xcfx86xe2x80x94CH2xe2x80x94, xcfx86xe2x80x94COxe2x80x94, xcfx86xe2x80x94CH2xe2x80x94CO2xe2x80x94 and xe2x80x94COxe2x80x94Oxe2x80x94C(CH3)3; it is preferred that the protecting group be xcfx86xe2x80x94CH2xe2x80x94 or xcfx86xe2x80x94COxe2x80x94. The cyclization of the intermediate (VII) to the corresponding protected arylsulfone (VIII) and then the deprotection to the unsubstituted 9-arylsulfone (IX) all follow known methods. The protecting groups (PG) are readily removed by means well known to those skilled in the art. The unsubstituted 9-arylsulfone (IX) can then be substituted at the C3-position (R3, ring nitrogen atom) as well as on the indole nitrogen (RN) as is known to those skilled in the art. Alternatively, arylsulfone (VIII) can be alkylated with the desired RNxe2x80x94X substituent to give the protected indole (XI) which then is deprotected to give the desired substituted 9-arylsulfone (X). Useful R3 groups include of xe2x80x94H and C1-C2 alkyl; it is preferred that R3 be xe2x80x94H. Useful RN groups include of xe2x80x94H and C1-C4 alkyl; it is preferred that RN is xe2x80x94H, C1 alkyl and C2 alkyl. The invention here is not the process chemistry but rather the novel products produced.
The preferred protecting group for the intermediates (VI), (VII) and (VIII) are benzyl and benzamide though other groups are operable as is known to those skilled in the art.
The 9-arylsulfones (XI) are amines, and as such form acid addition salts when reacted with acids of sufficient strength. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The pharmaceutically acceptable salts are preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline. The preferred pharmaceutically acceptable salts include salts of the following acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH3xe2x80x94(CH2)nxe2x80x94COOH where n is 0 thru 4, HOOCxe2x80x94(CH2)Nxe2x80x94COOH where n is as defined above. aa
The 9-arylsulfones (XI) of the present invention are useful to treat anxiety, depression, schizophrenia, stress related disease, panic, a phobia, obsessive compulsive disorder, obeisity, post-traumatic stress syndrome and other CNS disorders. It is preferred that the 9-aryl sulfones (XI) be used to treat anxiety for depression. To treat these diseases the 9-arylsulfones (XI) are administered orally, sublingually, transdermally or parenterally to provide a dosage of about 0.1 to about 50 mg/kg/day. It is preferred that the dosage range be from about 0.1 to about 10 mg/kg/day. The 9-arylsulfones (XI) can be administered in divided doses either two, three or four times daily. It is preferred that the 9-arylsulfones (XI) be administered orally.
The exact dosage and frequency of administration depends on the particular 9-arylsulfone(s) used, the particular disease being treated, the severity of the disease being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the 9-arylsulfone (XI) in the patient""s blood and/or the patient""s response to the particular condition being treated.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, xe2x80x9cZ1xe2x80x9d or xe2x80x9cRixe2x80x9d where xe2x80x9cixe2x80x9d is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z1 would represent a bivalent variable if attached to the formula CH3xe2x80x94C(xe2x95x90Z1)H. Groups Ri and Rj would represent monovalent variable substituents if attached to the formula CH3xe2x80x94CH2xe2x80x94xe2x80x94C(Ri)(Rj)xe2x80x94H. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both Ri and Rj are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as Ci, where xe2x80x9cixe2x80x9d is the integer corresponding to the carbon atom number. For example, C6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term xe2x80x9cR6xe2x80x9d represents a variable substituent (either monovalent or bivalent) at the C6 position.
Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol xe2x80x9cxe2x80x94xe2x80x9d in general represents a bond between two atoms in the chain. Thus CH3xe2x80x94Oxe2x80x94CH2xe2x80x94CH(Ri)xe2x80x94CH3 represents a 2-substituted-1-methoxypropane compound. In a similar fashion, the symbol xe2x80x9cxe2x95x90xe2x80x9d represents a double bond, e.g., CH2=C(Ri)xe2x80x94Oxe2x80x94CH3, and the symbol xe2x80x9cxc2x0xe2x80x9d represents a triple bond, e.g., HCxc2x0Cxe2x80x94CH(Ri)xe2x80x94CH2xe2x80x94CH3. Carbonyl groups are represented in either one of two ways: xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94, with the former being preferred for simplicity.
Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear fashion by N*xe2x95x90C(CH3)xe2x80x94CHxe2x95x90CClxe2x80x94CHxe2x95x90C*H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by xe2x80x94N*xe2x80x94(CH2)2xe2x80x94N(C2H5)xe2x80x94CH2xe2x80x94C*H2.
A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, xe2x80x94C(X1)(X2)xe2x80x94 the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X1) which is xe2x80x9cbelowxe2x80x9d another substituent (X2) will be identified as being in the alpha (xcex1) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol xe2x80x9c - - - xe2x80x9d or xe2x80x9c . . . xe2x80x9d. The corresponding substituent attached xe2x80x9cabovexe2x80x9d (X2) the other (X1) is identified as being in the beta (xcex2) configuration and is indicated by an unbroken or solid line attachment to the carbon atom.
When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable Ri attached to a carbon atom as xe2x80x94C(=Ri)xe2x80x94 might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (xe2x80x94COxe2x80x94) or as two separately attached monovalent variable substituents a-Ri-j and xcex2-Ri-k. When a bivalent variable, Ri, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form xe2x80x9ca-Ri-j:xcex2-Ri-kxe2x80x9d or some variant thereof. In such a case both a-Ri-j and xcex2-Ri-k are attached to the carbon atom to give xe2x80x94C(a-Ri-j)(xcex2-Ri-k)xe2x80x94. For example, when the bivalent variable R6, xe2x80x94C(=R6)xe2x80x94 is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are a-R6-1:xcex2R6-2, . . . a-R6-9:xcex2-R6-10, etc, giving xe2x80x94C(a-R6-1)(xcex2-R6-2)xe2x80x94, . . . xe2x80x94C(a-R6-9)(xcex2R6-10)xe2x80x94, etc. Likewise, for the bivalent variable R11, xe2x80x94C(=R11)xe2x80x94, two monovalent variable substituents are a-R11-1:xcex2R11-2. For a ring substituent for which separate a and xcex2 orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the a and xcex2 designations are omitted.
Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula xe2x80x94C1(Ri)Hxe2x80x94C2(Rj)Hxe2x80x94 (C1 and C2 define arbitrarily a first and second carbon atom, respectively) Ri and Rj may be defined to be taken together to form (1) a second bond between C1 and C2 or (2) a bivalent group such as oxa (xe2x80x94Oxe2x80x94) and the formula thereby describes an epoxide. When Ri and Rj are taken together to form a more complex entity, such as the group xe2x80x94Xxe2x80x94Yxe2x80x94, then the orientation of the entity is such that C1 in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designation xe2x80x9c . . . Ri and Rj are taken together to form xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94 . . . xe2x80x9d means a lactone in which the carbonyl is bonded to C2. However, when designated xe2x80x9c . . . Rj and Ri are taken together to form xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 the convention means a lactone in which the carbonyl is bonded to C1.
The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as xe2x80x9cC1-C4xe2x80x9d, where both xe2x80x9c1xe2x80x9d and xe2x80x9c4xe2x80x9d are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, xe2x80x9cC1-C4 alkylxe2x80x9d represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxycarbonyl describes a group CH3xe2x80x94(CH2)nxe2x80x94Oxe2x80x94COxe2x80x94 where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the xe2x80x9cCi-Cjxe2x80x9d designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C1-C3)alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because the xe2x80x9cC1-C3xe2x80x9d refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 alkoxyalkyl and (C1-C3)alkoxy(C1-C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.
All temperatures are in degrees Centigrade.
HPLC refers to high pressure liquid chromatography.
DMSO refers to dimethylsulfoxide.
DMF refers to dimethylformamide.
Saline refers to an aqueous saturated sodium chloride solution.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
IR refers to infrared spectroscopy.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from tetramethylsilane. xe2x80x94xcfx86 refers to phenyl (C6H5).
MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M+H]+ refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.
HRMS refers to high resolution mass spectrometry.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).